7-methylene-3alpha, 5-cyclo-6-ketone steroids and process for producing same



United States Patent 3,384,645 7-METHYLENE-3a,5-CYCLO-6-KETONE STEROIDSAND PROCESS FOR PRODUCING SAME Derek Burn and Vladimir Petrow, London,England, assignors to The British Drug Houses Limited No Drawing. FiledNov. 22, 1965, Ser. No. 509,170 Claims priority, application GreatBritain, Dec. 3, 1964, 49,166/64 6 Claims. (Cl. 260-3973) ABSTRACT OFTHE DISCLOSURE New 7-methylene-3a,5-cyclo-6-ketone steroids and processfor producing same comprising reacting a corresponding steroidal3a,5-cyclo-6-ketone with formaldehyde and the salt of a secondary amine.

This invention is for improvements in or relating to organic compoundsand has particular reference to a novel class of steroidal derivativeshaving a methylene group at position seven.

It is an object of the present invention to provide novel steroidalmaterials having a 7-methylene group, which may be represented by thepartial Formula I. The compounds of the present invention of partialFormula I are of value on account of their biological properties. Thus,for example, the derivatives of 17/3-hydroxy androstane which mayadditionally be substituted at C may possess anabolic and claudogenicproperties. The derivatives of 17a-acyloxypregnan-ZO-one, which fallwithin the scope of the present invention, may possess claudogenic andprogestational properties. The compounds of the present invention arealso of value as intermediates.

with formaldehyde and the salt of a secondary amine.

The starting materials, having the partial structure (II) are readilyprepared by methods well known in the art to which this inventionpertains and are described, for example, in Steroids, Fieser & Fieser,Reinhold Publishing Corp. New York, pp. 314 et seq. In carrying out theprocess of the present invention the starting material, having thepartial structure (II), is submitted to a Mannich type reaction withformaldehyde, conveniently in the form of its solid polymerpar-aformaldehyde, and a salt of a secondary amine such, for example, asdimethylamine hydrochloride, diethylamine hydrochloride or piperidine3,384,645 Patented May 21, 1968 "ice hydrochloride in an inert solventsuch as a lower aliphatic alcohol or dioxan. The reaction is preferablycarried out at temperatures between to 100 C., when it is generallycomplete in l to 6 hours. It is a surprising feature of the presentinvention that the product obtained is a 3a,5-cyclo-7-methylene-6-one,and not the anticipated aminomethylated product normally formed in aMannich reaction.

The process of the invention may be applied to a wide variety ofsteroidal 3a,5-cycl0-6-0nes which may be of the androst-ane,19-norandrostane, pregnane, l9-nor-pregnane, cholestane and spirostaneseries, additioally substituted by such groups as:

Hydroxyl and acyloxy groups and functional derivatives thelCOf at C11,C12, C14, C15, C16, C17, C20 and C21, including the condensationproducts of 16oz,17a-glyC0lS with carbonyl components.

Carbonyl groups at C11, C12, C15, C16, C17 and C20 which may requireconversion into a protected form prior to application of the process ofthe present invention. Such protected forms may include the derivedhydroxycompound, ketals, enol ethers and enamines.

Alkyl groups, and in particular methyl groups at C C C C and C and ethylgroups at C Lactone and ether residues such as O.CO.CH .CH at C ethergroups at C and bridging C and C Halogen groups such as chlorine andfluorine at C C16 and C21.

Unsaturated linkages, for example, at C Following is a description byway of example of methods of carrying the invention into effect.

Example l.17a-methyl-7-methylene-3a,S-cycl0- androstan-17B-ol-6-one MeMe Me i A To a solution of magnesium methyl bromide (prepared frommethyl bromide (8 ml.) and magnesium turnings (3.3 g.)) in dry etherml.) was added a solution of 6fl-hydroxy-3,S-cycloandrostan-17-one (10g.) (Ber., 1942, 75, 591) in dry ether ml.) and the mixture was stirredat room temperature overnight. Aqueous ammonium chloride was added, theether layer was separated, washed with water, dried (Na SO andevaporated. crystallisation of the residue from acetone gavemethyl-3a,5-cycloandrostane-6B,l7B-diol, M.P. 170-172 C., [a] +13.5 (c.,1.1 in dioxan).

A solution of the foregoing product (7 g.) in pyridine (70 ml.) wasadded to a suspension of the complex prepared from chromium trioxide (7g.) and pyridine (70 ml.) and the mixture was kept at room temperatureovernight. The precipitate was filtered olf and washed with ethylacetate. The combined filtrate and washings were washed with dilutehydrochloric acid, dilute sodium carbonate and water, dried (Na SO andevaporated to dryness. crystallisation of the residue from methanol gave17a-methyl-3u,5-cycloandrostan-17/3-ol-6-one, M.P. 203- 205 C., [a]|l1.2 (c. 0.7 in chloroform).

A mixture of the foregoing product (2 g.), paraformaldehyde (1 g.),dimethylamine hydrochloride (3.4 g.) and dry dioxan (30 ml.) was heatedunder reflux for 3 /2 hours and then poured into Water. The precipitatedsolid was recrystallised from diisopropyl ether to give 170:- methyl7-methylene 3a,5-cycloandrostan 17B-ol-6-one M.P. 147-1475 C., [a] +1O.Z(c. 1.0 dioxan). The compound has some anabolic properties and noandrogenic properties.

Example 2.-17/3-acetoxy-7-methyleue-3 a,5-cycloandrostan-6-one A0 Me 1 Amixture of 17 3-acetoxy-3u,5-cycloandrostan-6-one (2 g.) (J. Chem. Soc.,1957, 4105), paraformaldehyde (1 g.), dimethylamine hydrochloride (3.4g.) and dioxan (25 ml.) was heated under reflux for 1 hours. The productobtained on pouring the reaction mixture into water was crystallisedfrom methanol to give 17;3-acetoxy-7-methylene-3a,5-cycloandrostan-6-one, M.P. 123-124 C., [a] -|-36.7 (c.0.5 in dioxan).

Example 3.17a-acetoxy-7-methylene-3a,5-cyclopregnane-6,2()-dione Asolution of 17a-acetoxy-3B-p-toluenesulphonyloxypregn -en-20-one(prepared from 17aacetoxy-3B-hydroxy-pregn-5-en-20-one by treatment withp-toluenesulphonyl chloride in pyridine) (14 g.) and sodium citrate (17g.) in acetone (200 ml.) and water (200 ml.) was heated under reflux for8 hours. The product obtained on diluting the solution with water wascrystallised from methanol to give17a-acet0xy-3a,5-cyclopregnan-6fl-ol-20- one, M.P. 204-205" C., [aJ 20.3(c. 1.0 in dioxan).

A solution of the foregoing product (10 g.) in pyridine (100 ml.) wasadded to a suspension of the complex prepared from chromium trioxide (10g.) in pyridine (100 ml.), and the mixture was kept at room temperatureovernight. The precipitate was filtered 01f and washed with hot ethylacetate. The combined fil-trate and Washings were washed with diluteaqueous hydrochloric acid, aqueous sodium carbonate and water, dried (NaSO and evaporated to dryness. crystallisation of the residue frommethanol gave 17a-acetoxy-3a,5-cyclopregnane-6,20 dione, M.P. 225 C.,[11],; +15.2 (c. 0.95 in dioxan).

A mixture of the foregoing product (5 g.), paraformaldehyde (2 g.),dimethylamine hydrochloride (10 g.) and dry dioxan (100 ml.) Was heatedunder reflux for 2 /2 hours and then poured into water. crystallisationof the precipitated solid from methanol gave 17a-acetoxy-7-methylene-3a,S-cyclopregnane-6,20-dione, M.P. 197 C., +11.6 (c. 1.0 indioxan).

4 Example 4.7-methylene-3a,5-cycloandrostane 6, 17-dione 0 Me ll max.

233-4 III/4 (6, 12,390). Example5.7-methylene-3a,5-cyclopregnane-6,20-dione Alto A mixture of30:,5-cyclopregnane-6,20-dione (19 g.) (Goutarel, Cave, Tan and Leboeuf,Bull. Soc. Chim. France, 1962, 646), paraformaldehyde (6 g.) and dimethylamine hydrochloride (19 g.) in dry dioxan (400 ml.) was heatedunder reflux for 2 /2 hours, and then poured into water. The productpurified from ether to give 7-methylene-3a,5-cyclopregnane-6,20-dione,M.P. 141 C., +107 (c. 0.9 in chloroform),

k 23 my. (6, 9080).

max.

We claim:

1. a methyl 7 methylene 311,5 cycloandrostan- 17/8-ol-6-one.

2. 17fi-acetoxy-7-methylene3a,5-cycloandrostan-6-one.

3. 17oz acetoxy 7 methylene 3a,5 cyclopregnane- 6,20-dione.

4. 7-methylene-3a,5-cycloandrostane-6,17-dione.

5. 7-methylene-3a,S-cyclopregnane-6,20-dione.

6. A compound of the formula wherein X represents a C-17 substituentselected from the group consisting of where R is H or lower alk noyl andR is H or lower Refere es Cited alkyl; UNITED STATES PATENTS f?3,049,555 8/1962 Tyner 260397.4 5 3,205,243 9/ 1965 Riano et a1.260397.4 where R; is H, hydroxy or lower alkanoyloxy; and LEWIS GOTTS, nExaminen f T. MESHBESHER, Assistant Examiner.

